The Model Organisms Core will employ two genetically-tractable systems, the yeast S. cerevisiae and the zebrafish D. rerio, each with distinct advantages. These experimental systems will help dissect fundamental aspects of kidney development and protein structure and function. Experiments associated with these model systems will be complemented by the use of small molecule modulators that have emerged from Core associated activities over the past four years. Hypotheses arising from the unique attributes of the yeast and zebrafish models and from the use of chemical modulators will continue to be tested in higher cell types and organisms via the other Cores. In turn, experiments using yeast and zebrafish provide rapid assessments of predictions from more complex systems. The goals of the Yeast Core are to develop and continue to utilize established expression systems for wild type and disease-causing proteins that transit the secretory pathway in kidney cells. Genomic and proteomic attacks will identify factors that impact their biogenesis, and the mechanism of action of these factors will be established. Toward these goals, the Yeast Core has created over a dozen expression systems and offers collaborators the expertise and tools to co-opt this model organism. Specific assays developed in the Core include methods to assess how chaperones, the ubiquitin proteasome pathway, autophagy, and chemical chaperones impact secretory protein biogenesis. The Zebrafish Core will utilize established transgenic kidney reporter lines and to utilize established automated screening technologies in small molecule screens to identify chemical probes for kidney development and disease. The Zebrafish Core has a number of transgenic lines and identified small molecules that impact kidney development, and has pinpointed when specific factors act during kidney development. Collaborators will be able to establish and analyze results from newly created zebrafish lines and perform small molecule screens. Overall, the knowledge gained from the use of these complementary model organisms will be expanded via collaborations with the other Cores, and in turn the hypotheses that arise from more complex systems can be rapidly and in some cases more thoroughly tested in yeast and zebrafish. The Core will co-